Summary of work: Normal aging is associated with loss of lean body and muscle mass and strength. There are also increases in body fat, deterioration in lipid profiles and glucose intolerance (risk factors for heart diseasse) and reductions in cardiac function and fitness, immune function, and skin thickness. Reductions in sex steroid hormones, testosterone (T) in men and estradiol (E2) in women as well as growth hormone (GH) and its primary messenger, insulin like growth factor I (IGF-I), with age may contribute to these changes in body composition. Prior studies have shown partial reversal of age-related changes when rhGH was given to older persons. We recently completed study in women (n=52) and men (n=71), ages 65-88 y examining the effects of GH and sex steroid hormone replacement over a 6 month period, alone and combined, on body composition, skeletal muscle (strength, biochemistry, molecular biology), bone biochemistry, endocrine physiology (including plasma leptin, a hormone secreted by fat cells which influences satiety and energy metabolism), glucose and lipid metabolism, measures of gonadal, immune, renal, cardiac and arterial function, quality of life and psychological and sexual variables. Data analyzed so far has shown significant gains with GH and T, and less impressive increases with HRT in lean body mass, muscle strength, and aerobic capacity. GH and HRT also produced highly significant losses of abdominal and total body fat and improved total and LDL cholesterol. Adverse effects included increased blood sugar and insulin levels, joint symptoms, and edema, but no apparent effects on the prostate. We have also demonstrated decreases with both age and time in serum T in men in the Baltimore Longitudinal Study on Aging, suggesting that a trend from 1970 to 1995 for lower T in the population as a whole is contributing to the profound reduction of T observed in some older men. Another study has confirmed an association of high IGF- I levels with risk of prostate cancer, suggested a possible protective role for IGF-II, and shown that neither of these measures improves risk estimates obtained from measuring PSA. These studies are aimed at understanding (a) the potential clinical utility of interventions with GH and/or sex steroid hormones and (b) the cellular, biochemical, and molecular events responsible for, and resulting from, altered secretion of these hormones with age. Such investigations may lead to novel therapies to delay or ameliorate the deleterious effects of aging on the musculoskeletal system and other systems which contribute to frailty and loss of mobility in the elderly.Data from the GH/sex steroid intervention study will be analyzed in early to mid-FY 99. New studies are being planned, investigating the effects of an oral GH stimulating agent (GHRP analogue) on bone in osteoporotic women and men and on cardiovascular risk factors and cardiovascular function in older men and women with and without heart disease. - growth hormone, testosterone, estrogen, aging, body composition, muscle strength, glucose tolerance, lipids, bone - Human Subjects